Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized clinically and pathologically by injury to multiple tissues including the joints and the lungs. It is now well-established that RA-related autoantibodies (Abs) may be elevated in blood years prior to the onset of symptomatic inflammatory arthritis (IA), with this period of asymptomatic autoimmunity termed the 'preclinical' phase of RA. Importantly, the long duration of this preclinical period suggests that the immunologic processes that initiate RA are occurring at a site outside of the joints. This site is currently unknown; however, our central hypothesis is that lung is the site of initial generation of RA-related autoimmunity. This hypothesis is based on multiple observations including: (i) the association of inhaled factors such as tobacco smoke with increased risk for RA, (ii) published studies by ourselves and others demonstrating that lung disease, and in particular airways disease, is an early or even presenting manifestation of RA, (iii) the identification of plasma cells generating RA-related Abs within inducible bronchus-associated lymphatic tissue (iBALT) from patients with established RA (Rangel-Moreno et al 2006), (iv) our published work demonstrating a strong association between airways abnormalities and RA-related Ab elevations in subjects without RA but who are at high-risk for the future development of RA, and (v) our preliminary data using analyses of sputa in a unique cohort of subjects at high-risk for future RA to show that RA-related Abs appear to be generated in the lung. The primary objectives of this project are to establish that RA-related Abs are initially generated in the lung, and identify specific tissue changes in the lung that are associated with the generation of this autoimmunity. The secondary objective is to determine the relationship between RA-related autoimmunity and the progression of lung and joint disease. We will address these objectives by using our unique resources, including large cohorts of subjects at-risk for future RA, to perform these Specific Aims: 1) to characterize the phenotypes of RA-related Abs in sputa and sera from subjects during the natural history of RA, with a focus on the preclinical period of RA development, and 2) to evaluate the histology of lung tissue to identify factors that are associated the development of RA-related autoimmunity. Through these Aims, we expect to demonstrate that RA-related autoimmunity is generated in the lung in the absence of arthritis, specific Ab phenotypes are associated with the development and progression of lung and joint disease, and that specific immunologic changes in the lung including the presence of iBALT are associated with the generation of these Abs. We believe that these findings will provide important support for further studies of specific mechanisms of development of RA in the lungs that can ultimately be targeted for disease prevention.